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Background & Aims A detailed understanding of antitumor immunity is essential for optimal cancer immune therapy. Although defective mutations in the B2M and HLA-ABC genes, which encode molecules essential for antigen presentation, have been reported in several studies, the effects of these defects on tumor immunity have not been quantitatively evaluated. Methods Mutations in HLA-ABC genes were analyzed in 114 microsatellite instability–high colorectal cancers using a long-read sequencer. The data were further analyzed in combination with whole-exome sequencing, transcriptome sequencing, DNA methylation array, and immunohistochemistry data. Results We detected 101 truncating mutations in 57 tumors (50%) and loss of 61 alleles in 21 tumors (18%). Based on the integrated analysis that enabled the immunologic subclassification of microsatellite instability–high colorectal cancers, we identified a subtype of tumors in which lymphocyte infiltration was reduced, partly due to reduced expression of HLA-ABC genes in the absence of apparent genetic alterations. Survival time of patients with such tumors was shorter than in patients with other tumor types. Paradoxically, tumor mutation burden was highest in the subtype, suggesting that the immunogenic effect of accumulating mutations was counterbalanced by mutations that weakened immunoreactivity. Various genetic and epigenetic alterations, including frameshift mutations in RFX5 and promoter methylation of PSMB8 and HLA-A, converged on reduced expression of HLA-ABC genes. Conclusions Our detailed immunogenomic analysis provides information that will facilitate the improvement and development of cancer immunotherapy.

The mucosa of the body of the stomach (ie, the gastric corpus) uses 2 overlapping, depth-dependent mechanisms to respond to injury. Superficial injury heals via surface cells with histopathologic changes like foveolar hyperplasia. Deeper, usually chronic, injury/inflammation, most frequently induced by the carcinogenic bacteria Helicobacter pylori, elicits glandular histopathologic alterations, initially manifesting as pyloric (also known as pseudopyloric) metaplasia. In this pyloric metaplasia, corpus glands become antrum (pylorus)-like with loss of acid-secreting parietal cells (atrophic gastritis), expansion of foveolar cells, and reprogramming of digestive enzyme-secreting chief cells into deep antral gland-like mucous cells. After acute parietal cell loss, chief cells can reprogram through an orderly stepwise progression (paligenosis) initiated by interleukin-13-secreting innate lymphoid cells (ILC2s). First, massive lysosomal activation helps mitigate reactive oxygen species and remove damaged organelles. Second, mucus and wound-healing proteins (eg, TFF2) and other transcriptional alterations are induced, at which point the reprogrammed chief cells are recognized as mucus-secreting spasmolytic polypeptide-expressing metaplasia cells. In chronic severe injury, glands with pyloric metaplasia can harbor both actively proliferating spasmolytic polypeptide-expressing metaplasia cells and eventually intestine-like cells. Gastric glands with such lineage confusion (mixed incomplete intestinal metaplasia and proliferative spasmolytic polypeptide-expressing metaplasia) may be at particular risk for progression to dysplasia and cancer. A pyloric-like pattern of metaplasia after injury also occurs in other gastrointestinal organs including esophagus, pancreas, and intestines, and the paligenosis program itself seems broadly conserved across tissues and species. Here we discuss aspects of metaplasia in stomach, incorporating data derived from animal models and work on human cells and tissues in correlation with diagnostic and clinical implications.

Background Patients with inflammatory bowel diseases (IBD), specifically those treated with anti-tumor-necrosis-factor (TNF)α biologics are at high risk for vaccine preventable infections. Their ability to mount adequate vaccine responses is unclear. Aim To assess serologic responses to mRNA-COVID-19 vaccine, and safety profile, in patients with IBD stratified according to therapy, compared to healthy controls (HC). Methods Prospective, controlled, multi-center Israeli study. Subjects enrolled received two BNT162b2 (Pfizer/BioNTech) doses. Anti-spike antibodies levels and functional activity, anti-TNFα levels and adverse events (AEs) were detected longitudinaly. Results Overall 258 subjects: 185 IBD (67 treated with anti-TNFα, 118 non-anti-TNFα), and 73 HC. After the first vaccine dose all HC were seropositive, while ∼7% of patients with IBD, regardless of treatment, remained seronegative. After the second dose all subjects were seropositive, however anti-spike levels were significantly lower in anti-TNFα treated compared to non-anti-TNFα treated patients, and HC (both P, Graphical abstract

The article presents a literature review of the most common lysosomal storage diseases — Gaucher’s disease. This pathology is caused by a inherited deficiency in glucocerebrosidase that cleaves cerebrosides. Decrease glucocerebrosidase results in the sphingolipids accumulation in the reticuloendothelial system and the health cells are substituted by defective ones. We describe the clinical manifestations of the three forms of the disease, its diagnosis algorithms and advanced specific treatment.

Аріл-гідрокарбоновий рецептор (AhR) — фактор транскрипції, який активується великим числом факторів навколишнього середовища і може відігравати роль у патогенезі запальних захворювань кишечника у людини та в мишачих моделях. Ми вивчали можливість застосування симвастатину й антагоніста рецепторів інтерлейкіну-1 для фармакологічної корекції гострого ілеїту у щурів з акцентом на дослідженні інтенсивності експресії AhR лімфоцитами тонкої кишки. AhR-імунопозитивні лімфоцити визначали за допомогою методу непрямої імунофлюоресценції з використанням моноклональних антитіл щура. Ми встановили, що розвиток ілеїту супроводжувався зміною кількості AhR+-лімфоцитів і щільності їх на імунопозитивних клітинах. Застосування препаратів під час розвитку експериментальної патології супроводжувалося змінами експресії AhR та їх щільності на лімфоцитах.

У 49 хворих, у 20 з яких діагностовано поєднане ураження підшлункової залози (хронічний панкреатит у стадії загострення) та печінки (цироз печінки класу А, В за Чайльд — П’ю) алкогольної етіології, у 12 — хронічний панкреатит у стадії загострення без супутньої патології та в 17 — алкогольний цироз печінки аналогічної стадії без втягнення в процес підшлункової залози, проведено визначення концентрації фосфоліпази А2 типу ІІА та рівня колагену ІV у сироватці крові. Найбільш високу концентрацію фосфоліпази А2 типу ІІА виявлено у хворих із поєднаним алкогольним ураженням підшлункової залози та печінки (568,57 ± 30,34 пг/мл), що в 1,58 раза перевищувала її рівень в обстежених з ізольованим алкогольним ураженням підшлункової залози (Р < 0,05). У хворих на алкогольний цироз печінки класу А, В за Чайльд — П’ю концентрація фосфоліпази А2 типу ІІА становила (171,35 ± 22,46) пг/мл (у здорових — (123,00 ± 10,12) пг/мл). Відповідно до давності поєднаного ураження підшлункової залози та печінки (понад 5 років) рівень фосфоліпази А2 типу ІІА знижувався, тоді як концентрація колагену ІV зросла у 2,5 раза порівняно з таким показником у хворих при давності захворювання до одного року, а між ними був встановлений обернений кореляційний зв’язок середньої сили.

The article describes the main stages of the development of views on the diagnosis of chronic gastritis with highlighting the issue of diagnosis as an integral part of the set of measures concerning the timely detection of preneoplastic changes in the gastric mucosa. The main views on the development of carcinogenesis are presented based on current knowledge about the factors influencing the course of this process. Among known measures to prevent the development of precancerous changes, today the most important ones are the reliable stratification of risk groups in terms of their development and the strategy for identifying and eliminating Helicobacter pylori as a recognized factor of carcinogenesis. The development of bacterial resistance to basic medications recommended in the schemes of eradication therapy causes a further search of ways to enhance their effectiveness. As shown in a number of studies, the results of which are presented in the article, the most reliable is the inclusion of bismuth subcitrate (De-Nol) in the schemes of eradication.

Background & Aims Fecal microbiota transplantation (FMT) is an emerging treatment modality for ulcerative colitis (UC). Several randomized controlled trials have shown efficacy for FMT in the treatment of UC, but a better understanding of the transferable microbiota and their immune impact is needed to develop more efficient microbiome-based therapies for UC. Methods Metagenomic analysis and strain tracking was performed on 60 donor and recipient samples receiving FMT for active UC. Sorting and sequencing of immunoglobulin (Ig) A–coated microbiota (called IgA-seq) was used to define immune-reactive microbiota. Colonization of germ-free or genetically engineered mice with patient-derived strains was performed to determine the mechanism of microbial impact on intestinal immunity. Results Metagenomic analysis defined a core set of donor-derived transferable bacterial strains in UC subjects achieving clinical response, which predicted response in an independent trial of FMT for UC. IgA-seq of FMT recipient samples and gnotobiotic mice colonized with donor microbiota identified Odoribacter splanchnicus as a transferable strain shaping mucosal immunity, which correlated with clinical response and the induction of mucosal regulatory T cells. Colonization of mice with O splanchnicus led to an increase in Foxp3+/RORγt+ regulatory T cells, induction of interleukin10, and production of short chain fatty acids, all of which were required for O splanchnicus to limit colitis in mouse models. Conclusions This work provides the first evidence of transferable, donor-derived strains that correlate with clinical response to FMT in UC and reveals O splanchnicus as a key component promoting both metabolic and immune cell protection from colitis. These mechanistic features will help enable strategies to enhance the therapeutic efficacy of microbial therapy for UC. Clinicaltrials.gov ID NCT02516384 .

Backgrounds & Aims Increased permeability is implicated in the pathogenesis of intestinal disease. In vitro and in vivo studies have linked down-regulation of the scaffolding protein ZO-1, encoded by the TJP1 gene, to increased tight junction permeability. This has not, however, been tested in vivo. Here, we assessed the contributions of ZO-1 to in vivo epithelial barrier function and mucosal homeostasis. Methods Public Gene Expression Omnibus data sets and biopsy specimens from patients with inflammatory bowel disease (IBD) and healthy control individuals were analyzed. Tjp1f/f;vil-CreTg mice with intestinal epithelial–specific ZO-1 knockout (ZO-1KO.IEC) mice and Tjp1f/f mice littermates without Cre expression were studied using chemical and immune-mediated models of disease as well as colonic stem cell cultures. Results ZO-1 transcript and protein expression were reduced in biopsy specimens from patients with IBD. Despite mildly increased intestinal permeability, ZO-1KO.IEC mice were healthy and did not develop spontaneous disease. ZO-1KO.IEC mice were, however, hypersensitive to mucosal insults and displayed defective repair. Furthermore, ZO-1–deficient colonic epithelia failed to up-regulate proliferation in response to damage in vivo or Wnt signaling in vitro. ZO-1 was associated with centrioles in interphase cells and mitotic spindle poles during division. In the absence of ZO-1, mitotic spindles failed to correctly orient, resulting in mitotic catastrophe and abortive proliferation. ZO-1 is, therefore, critical for up-regulation of epithelial proliferation and successful completion of mitosis. Conclusions ZO-1 makes critical, tight junction–independent contributions to Wnt signaling and mitotic spindle orientation. As a result, ZO-1 is essential for mucosal repair. We speculate that ZO-1 down-regulation may be one cause of ineffective mucosal healing in patients with IBD.

BACKGROUND & AIMS: SIRT5 plays pleiotropic roles via post-translational modifications, serving as a tumor suppressor, or an oncogene, in different tumors. However, the role SIRT5 plays in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) remains unknown. METHODS: Published datasets and tissue arrays with SIRT5 staining were used to investigate the clinical relevance of SIRT5 in PDAC. Furthermore, to define the role of SIRT5 in the carcinogenesis of PDAC, we generated autochthonous mouse models with conditional Sirt5 knockout. Moreover, to examine the mechanistic role of SIRT5 in PDAC carcinogenesis, SIRT5 was knocked down in PDAC cell lines and organoids, followed by metabolomics and proteomics studies. A novel SIRT5 activator was utilized for therapeutic studies in organoids and patient-derived xenografts. RESULTS: SIRT5 expression negatively regulated tumor cell proliferation and correlated with a favorable prognosis in PDAC patients. Genetic ablation of Sirt5 in PDAC mouse models promoted acinar-to-ductal metaplasia, precursor lesions, and pancreatic tumorigenesis, resulting in poor survival. Mechanistically, SIRT5 loss enhanced glutamine and glutathione metabolism via acetylation-mediated activation of GOT1. A selective SIRT5 activator, MC3138, phenocopied the effects of SIRT5 overexpression and exhibited anti-tumor effects on human PDAC cells. MC3138 also diminished nucleotide pools, sensitizing human PDAC cell lines, organoids, and patient-derived xenografts to gemcitabine. CONCLUSIONS: Collectively, we identify SIRT5 as a key tumor suppressor in PDAC, whose loss promotes tumorigenesis through increased non-canonical utilization of glutamine via GOT1, and that SIRT5 activation is a novel therapeutic strategy to target PDAC.

Objective. The analysis of the literature has shown that in patients with chronic non-ulcerative colitis, there were isolated E.coli that cause dysentery-like, cholera-like diseases and escherichioses. Thus, the aim of our study was to establish the level of persistence of enteropathogenic Escherichia in the colon of patients with chronic non-ulcerative colitis and their importance in the ecological system «macroorganism — microbiota». Material and methods. During 2000–2015, there has been conducted a bacteriological examination of the colon content in patients with chronic non-ulcerative colitis aged 27–41 years (average age 37.74 ± 3.62 years). The resulting cultures were examined in the indicative agglutination tests with OKA polyvalent serum. Positive cultures were tested with polyvalent serum of narrow spectrum ОКВ, ОКС, ОКD and ОКЕ. Results. In patients, in colon cavity of which E.coli O18ac:K77; O26:K60; O55:K59; O128ab:K67 were detected, the disease occurs by nosology of colienteritis. In those patients, in whom O25:K11; O144:K; O124:K72 serotypes have been identified, disease occurred as bacterial dysentery, and O25:K11 and O128:K67 — in chole­ra-like form. Discussion. In 94.50 % of patients, common E.coli were detected, but in 55 (35.03 %) of them enteropathogenic Escherichia persist, in 41 (26.11 %) — E.coli Hly+, in 37 (23.57 %) — E.coli Lac–, in 18 (11.46 %) — enterotoxigenic E.coli, in 14 (8.42 %) — enteroinvasive, and in 11 (7.01 %) — enterohemorragic Escherichia. Conclusions. It was determined that the main serotypes of opportunistic Escherichia, which colonize and persist in the colon cavity of patients with chronic non-ulcerative colitis, were O114:K90; O25:K11; O124:K72; O128:K67; O18ac:K77, the persistence of which affects clinical manifestation from colitis to dysentery-like or cholera-like disease.

Background. The pathogenesis of chronic inflammatory bowel disease (IBD) is still not fully clarified. It is known that disorders of the intestinal microbiota lead to an increased intestinal permeability, activation of mucous and adaptive immunity, impaired production and intestinal absorption of short-chain fatty acids (SCFA). The ratio of acetic, propionic, butyric acids is an important indicator of the integrity of the intestinal microbial community. Thus, the study of the composition of the intestinal microbiota and the concentrations of fecal SCFA is a very promi­sing approach to broadening the understanding of IBD pathoge­nesis. The purpose of our study was to determine the features of the production of fecal SCFA and the composition of colon microbiota in patients with IBD. Materials and methods. The study, which was carried out at the Department of Intestinal Diseases of the Institute of Gastroenterology of the National Academy of Medical Sciences of Ukraine, involved 74 patients with IBD with an average age of (43.2 ± 1.8) years, who according to nosology were divided into 2 groups: group I — those with ulcerative colitis (UC) (n = 66), group II — individuals with Crohn’s disease (CD) (n = 8). The diagnoses of CD and UC were established accor­ding to generally accepted diagnostic standards in gastroenterology. Determination of fecal SCFA was carried out by chromatographic method with the use of hardware-software complex for medical researches on the basis of the gas chromatographer Chromateс Crystal 5000. The intestinal microflora was evaluated using a microbiological study of the colon content. Results. Patients with IBD had significant changes in the spectrum of SCFA, which were similar in both UC and CD: a decrease in acetic acid in the UC group by 5.7 times, in the CD group by 10.5 times (p, Актуальність. Патогенез хронічних запальних захворювань кишечника (ХЗЗК) досі залишається до кінця не вивченим. Відомо, що порушення мікробіоти кишечника призводять до підвищеної проникності кишечника, порушення продукції та кишкового всмоктування коротколанцюгових жирних кислот (КЖК), співвідношення яких є важливим показником цілісності мікробної спільноти кишечника. Таким чином, вивчення складу мікробіоти кишечника і концентрацій фекальних КЖК є дуже перспективним підходом до розширення розуміння патогенезу ХЗЗК. Метою дослідження було визначити особливості продукції фекальних КЖК та складу мікробіоти товстої кишки у хворих на ХЗЗК. Матеріали та методи. У дослідження, що проводилось у відділенні захворювань кишечника ДУ «Інститут гастроентерології НАМН України», були залучені 74 пацієнти з ХЗЗК, які були розподілені на 2 групи: І група — хворі на неспецифічний виразковий коліт (НВК) (n = 66), II — хворі на хворобу Крона (ХК) (n = 8). Діагнози ХК та НВК були встановлені згідно із загальноприйнятими стандартами діагностики в гастроентерології. Проведене визначення фекальних КЖК, дослідження видового та кількісного складу мікрофлори вмісту кишечника. Результати. У хворих на ХЗЗК виявлені значні зміни в спектрі КЖК, які були аналогічними як при НВК, так і при ХК: зменшення вмісту оцтової кислоти в групі НВК у 5,7 раза і в групі ХК у 10,5 раза (р

Актуальность. Хронический атрофический гастрит (ХАГ) относится к предраковым заболеваниям желудка, на фоне которого часто наблюдаются кишечная метаплазия и дисплазия, а также чаще, чем у здоровых лиц, может возникать рак желудка. Цель исследования: изучить факторы риска ХАГ и их взаимосвязь с выраженностью морфологических изменений слизистой оболочки желудка. Материалы и методы. Под наблюдением находились 120 пациентов с ХАГ. Все больные проходили эндоскопическое (с функцией NBI), морфологическое обследование и анкетирование с помощью анкеты, которая была разработана для больных с ХАГ с целью изучения факторов риска. Результаты. Были определены значимые факторы развития предраковых изменений слизистой оболочки желудка, среди которых на первый план выступили показатели, которые характеризуют острый (r = 0,593) и хронический стресс (r = 0,544), употребление чрезмерного количества жареных (r = 0,636), копченых (r = 0,512) и маринованных (r = 0,591) продуктов, возраст (r = 0,639), ІІ группа крови (r = 0,651), онконаследственность (r = 0,533), наличие дуоденогастрального рефлюкса (r = 0,524) и патологии щитовидной железы (r = 0,522). По результатам эндоскопического и морфологического исследований выявлено уменьшение частоты Helicobacter pylori-инфицирования по мере роста перестроечных изменений слизистой оболочки желудка (атрофия — метаплазия — дисплазия). Выводы. Установлено возможное влияние таких факторов риска, как стресс, возраст, группа крови, наследственность, употребление чрезмерного количества жареных, копченых и маринованных продуктов, заболевания щитовидной железы и наличие дуоденогастрального рефлюкса на развитие ХАГ.

Background. The diagnosis of IgG4-associated sclerosing disease, IgG4-associatied condition, is based on a comprehensive evaluation of characteristic clinical, radiographic, serologic, histological and immunohistochemical features. The histopathological is the main examination in the diagnosis of IgG4-associatied diseases. The purpose of the study was to evaluate the state of IgG4-positive plasma cells in the mucosa of the colon in patients with established morphological and endoscopic diagnosis of ulcerative colitis (UC) and Crohn’s disease (CD). Materials and methods . The study used biopsies material from 14 patients treated at the Institute of Gastroenterology, in the department intestine diseases, with established morphological and endoscope diagnosis of UC (8) and CD (6) in the acute stage. All patients had no evidence of autoimmune pancreatitis type I and II. Biopsy were fixed in 10.0% neutral formalin, dehydrated in alcohols of increasing concentration and embedded in paraffin for histological studies. Histological sections of 3–5 µm were colored with hematoxylin and eosin. There were used monoclonal IgG4 antibodies for immunohistochemical studies (Abcam, USA). Results . Our results show that with ulcerative colitis in 37.5 % of cases IgG4-positive plasma cells in the colon mucosa have not been identified. In 25 % of cases, sporadic IgG4-positive plasma cells were identified. In 37.5 % of cases, the groups of IgG4-positive plasma cells not exceeding 5 cells in one group were found. In Crohn’s disease, groups of IgG4-positive plasma cells were observed in all cases, in addition it should be noted that the group included 10 or more cells. Conclusions. It is shown that in UC, IgG4-positive plasma cells may be absent, solitary or gathered in small groups to 5 cells, and in CD, the groups consisting of 10 or more cells are observed.

Background. The differentiation of mild (F1-F2) and advanced fibrosis (F3-F4), as well as the exclusion of fibrosis in patients with nonalcoholic fatty liver disease (NAFLD), are extremely important for prediction of the disease course. Integrative analyses of serum markers have been proposed as promising alternatives to biopsy method. Our study was targeted to develop a new model for determining the stage of fibrosis based on a more efficient combination of serological markers and to compare it with well-established algorithms. Materials and methods. Sixty patients with biopsy-proven NAFLD, including 26 (43 %) men and 34 (57 %) women, with average age of 37.10 ± 12.4 and 44.30 ± 7.25 years, respectively, were recruited for the study. Particularly, advanced fibrosis was diagnosed in 8 patients, 28 had mild fibrosis and 24 didn’t have any fibrosis according to morphological study. The following fibrosis markers were calculated: aspartate aminotransferase and alanine aminotransferase ratio (AAR), aspartate aminotransferase to platelet ratio index (APRI), fibrosis index based on the 4 factor (FIB-4). Among many variables, hyaluronic acid, α2-macroglobulin, apolipoprotein A1, fibronectin, and haptoglobin were included in comprehensive study. Integrative model have been built up to determine the stage of fibrosis. The models were compared with the area under the receiver operating characteristic (AUROC) curves. Results. The ROC analysis showed that the FIB-4 demonstrated the largest AUROC, for the F2 — 0.72, F3 — 0.8, F4 — 0.82, respectively. Obtained results of the APRI were significantly higher for mild and advanced fibrosis (F2 — 0.74, F3 — 0.82). The AAR values were reliable only for liver cirrhosis (AUROC 0.89). A strong direct correlation was determined between the stage of fibrosis and the level of hyaluronic acid, α2-macroglobulin and fibronectin (r = 0.72, 0.93 and 0.71, p < 0.05, respectively). Whereas, we observed a moderate negative linear correlation between fibrosis stage and the indices of both apolipoprotein A1 and haptoglobin (r = –0.61; r = –0.35, respectively, p < 0.05). The positive correlation was determined between activity of the inflammatory process and the content of hyaluronic acid, α2-macroglobulin and fibronectin (r = 0.54, 0.67 and 0.55 at p < 0.05), while the reverse moderate relation observed for apolipoprotein A1 and hapthoglobin (r = –0.56 and –0.33, p < 0.05). Conclusions. The analysis of obtained results showed that α2-macroglobulin, apolipoprotein A1, hyaluronic acid, and fibronectin had the greatest diagnostic validity among non-invasive markers of fibrosis. Every of them get the AUROC level higher than 0.75 for minimal fibrosis and, moreover, for moderate, significant fibrosis and cirrhosis they had an area more than 0.9.

Background . The article deals with the chronic inflammatory bowel diseases, in particular, the attention is paid to ulcerative colitis (UC). UC proceeds with the development of a number of extraintestinal lesions, among which a special place is given to the changes in the liver and bile ducts. In connection with this, a study was conducted to assess the prevalence, nature and clinical features of liver damage in patients with UC. Materials and methods. Under observation, there were 180 patients with UC confirmed endoscopically and morphologically. All patients underwent multimodal ultrasound examination of the liver, study of the biochemical signs of cytolysis and/or cholestasis with negative serological markers of viral hepatitis B, C, D and autoimmune hepatitis. Also, a biochemical study of the lipid spectrum of the blood was performed, and in patients with suspected autoimmune lesions of the liver — an analysis of the spectrum of the corresponding antibodies. Results. In 180 patients with UC, a liver damage was detected in 58 (32.2 %) persons. Parenchymal lesions of the liver were diagnosed in 40 (22.2 %) UC patients, and changes in the bile ducts — in 18 (10.0 %) patients with UC. Nonalcoholic steatohepatitis (NASH), autoimmune hepatitis (AH) and primary biliary cirrhosis (PBC) of the liver were detected in 40 (69.0 %) patients with UC, and lesions of extra- and intrahepatic bile ducts and gall bladder — in 18 (31.0 %). Among the parenchymal lesions of the liver, NASH dominated (53.5 %). AH was diagnosed in 8.6 % of patients, PBC — in 5.2 % of patients with UC. All patients with UC and NASH, in addition to the basic UC therapy, received the preparation of essential phospholipids in a daily dose of 1,800 mg (2 capsules 3 times a day) for three months. After the end of treatment, only 2 (6.5 %) patients had minor complaints. Prior to treatment, a significant increase in aspartate aminotransferase and alanine aminotransferase by 2.3 and 2.2 times, respectively, was observed in all the examined patients, in combination with 3.7 times increase in gamma-glutamyl transpeptidase compared with the norm, which may indicate a moderate cytolysis syndrome. After the treatment, patients showed a tendency to normalize the enzymatic status, although the indices remained elevated in comparison with the norm. Conclusions. Thus, liver damage was detected in 32.2 % of patients, predominantly in the advanced forms, with a moderate and severe course and high activity of UC. For the treatment of NASH in patients with UC, it is advisable to use essential phospholipids.

Morphological analysis of the microstructural changes of hepatocytes has been performed in patients with chronic C viral hepatitis; the distribution of apoptosis markers and cytoskeletal proteins has been analyzed on the material of 41 liver biopsies. Using immunohistochemical analysis and computer morphometry there have been investigated microstructural changes which accompany the progression of fibrosis, particularly the mechanisms of hepatocytes apoptosis, localization of cytochrome C, microfilaments changes and contractile properties of actin with parallel activation of regeneration processes.

Метаболічне ураження печінки часто супроводжує захворювання різних систем організму. Неалкогольна жирова хвороба печінки (НЖХП) — найбільш поширена патологія, що пов’язана з інсулінорезистентністю, цукровим діабетом та ожирінням. Поширеність НЖХП коливається залежно від різних факторів, серед яких — етнічне походження, вік, наявність метаболічного синдрому. Дані епідеміологічних досліджень останніх років свідчать, що жировий гепатоз майже в два рази частіше спостерігається у чоловіків порівняно з жінками дітородного віку. Відомо, що статеві гормони є важливими регуляторами обміну ліпідів і відповідають за гендерний диморфізм ліпідного профілю. У статті наведений огляд наукових досліджень щодо визначення ролі естрогенів у розвитку НЖХП на різних етапах її патогенезу: накопичення жирів, запалення та розвитку фіброзу.

Актуальность. Хронические воспалительные заболевания кишечника (ХВЗК), а именно неспецифический язвенный колит (НЯК) и болезнь Крона (БК), остаются одной из наиболее сложных и актуальных проблем гастроэнтерологии во всем мире. В настоящее время остается недостаточно изученным вопрос о влиянии микрофлоры кишечника и ее изменений на развитие и прогрессирование воспалительного процесса. Однако наиболее доминирующая этиологическая гипотеза говорит о том, что ХВЗК являются результатом аномального иммунного ответа на измененную микробиоту кишечника под воздействием факторов окружающей среды или патогенных микроорганизмов у генетически склонного хозяина. Изменения микробиоты при ХВЗК общепризнаны, но зависимость этих изменений от возраста пациентов еще нуждается в исследовании. Цель исследования: изучить особенности дисбиоза кишечника и частоты синдрома избыточного бактериального роста (СИБР) у пациентов с ХВЗК в зависимости от нозологии и возраста. Материалы и методы. Обследовано 120 пациентов с ХВЗК в возрасте от 19 до 79 лет, в среднем (43,90 ± 1,40) года; среди них 83 больных НЯК, 37 — БК. Все больные были разделены на группы в зависимости от нозологии и возраста. Больным были проведены водородный дыхательный тест для выявления СИБР, бактериологическое исследование кала и хроматография короткоцепочечных жирных кислот (КЖК) в копрофильтратах. Результаты. Установлены наличие глубоких изменений качественного и количественного состава микрофлоры толстой кишки и высокая частота выявления СИБР у пациентов с ХВЗК. Выявлена зависимость изменений состава микрофлоры тонкой и толстой кишки у больных от возраста и нозологии. Снижение концентрации бифидобактерий в содержимом толстого кишечника выявляли чаще всего у пациентов молодого возраста с БК, тогда как снижение количества лактобактерий чаще определялось у больных пожилого возраста в обеих нозологических группах. С возрастом росла частота выявления гемолитических биоваров кишечной палочки, условно-патогенных энтеробактерий и грибов рода Candida. Наблюдались изменения как суммарного общего содержания, так и показателей отдельных КЖК относительно здоровых лиц, что свидетельствовало об угнетении метаболической активности нормальной микрофлоры. Снижение уровней уксусной и масляной кислоты указывало на выраженное угнетение продуцентов этих метаболитов. Выводы. Выявлено, что больные пожилого возраста более склонны к развитию СИБР, снижению концентрации лактобактерий в содержимом толстой кишки, а также увеличению частоты выявления условно-патогенных энтеробактерий и грибов рода Candida. У больных молодого возраста преимущественно выявляется субкомпенсированная форма дисбиоза со снижением концентрации бифидобактерий. С возрастом также наблюдается угнетение продуцентов уксусной и масляной кислоты. Результаты данных исследований предоставят возможность клиницистам более тщательно подбирать терапевтическую тактику, а именно повлияют на выбор препаратов, которые модулируют микробиоту кишечника, с учетом не только нозологической формы, но и возраста пациента.

В статье рассматриваются вопросы, связанные с кишечной микрофлорой и короткоцепочечными жирными кислотами у больных с синдромом раздраженного кишечника. Установлено, что концентрация уксусной, пропионовой, масляной кислот в кале выше у больных с синдромом раздраженного кишечника с диареей по сравнению с больными без диарейного синдрома. У 83,3–88,9 % больных с различными формами синдрома раздраженного кишечника наблюдаются дисбиотические изменения; у пациентов с диарейной формой чаще отмечается пониженное содержание бифидобактерий и, особенно, лактобактерий. Отмечается определенная взаимозависимость между концентрацией короткоцепочечных жирных кислот и содержанием бифидобактерий, лактобактерий, кандидозной и условно-патогенной флоры.

Background. The problem of the development and progression of chronic diffuse liver diseases is currently one of the most important in modern gastroenterology, it has general medical and social significance. The purpose was to determine the features of indicators of the functional state of the liver, immune link, cytokine regulation and carbohydrate metabolism in patients with alcohol-related and drug-induced chronic diffuse liver diseases. Materials and methods. There were 50 patients with chronic diffuse liver diseases under the supervision: 27 patients with alcoholic liver disease — 16 (59.3 %) men and 11 (40.7 %) women with the ave­rage age of (37.6 ± 2.4) years; and 23 individuals with toxic drug-induced hepatitis — 6 (26.1 %) men and 17 (73.9 %) women aged (49.2 ± 3.1) years. All patients underwent biochemical and immunological blood tests. The levels of interleukin 6 (IL-6), IL-10, tumor necrosis factor α (TNF-α), and the HOMA-IR were also determined. Results. Most patients with alcoholic liver disease and toxic drug-induced hepatitis are characterized by the presence of cytolytic and cholestatic syndromes, mainly of a minimal degree of activity. Signs of hypercoagulation were found 2 times more often among patients with alcoholic liver disease than among those with toxic drug-induced hepatitis (χ2 = 4.43; p < 0.05). In drug-induced liver injury, an increase in the level of prothrombin index was observed 6.5 times more often (χ2 = 10.87; p < 0.01). A significant 1.8-fold decrease in the number of T-killers (p < 0.05) was found in patients with drug-induced liver injury compared to the control group, while in patients with alcoholic liver disease, the activation of the humoral immunity was determined. There was a significant increase in IL-6, TNF-α, the ratio of pro-inflammatory and anti-inflammatory cytokines, the development of insulin resistance in persons with alcohol-related liver damage, while a significant decrease in IL-10 was typical for patients with toxic drug-induced hepatitis. Conclusions. The analysis of the features of the functional state of the liver, immune link, cytokine regulation and carbohydrate metabolism in the examined patients revealed indicators that can be considered laboratory markers for the development and progression of toxic liver lesions.

Background. Today, the development and implementation of non-invasive methods for the diagnosis of ulcerative colitis is certainly an actual task of the scientific community, the solution of which will allow us to prescribe the adequate treatment in time and to improve the quality of life of patients. Given that the differences between women and men in the parameters determining the state of health are generally recognized, the purpose of the work was to determine the gender characteristics of the level of biological markers of intestinal inflammation in patients with ulcerative colitis. Materials and methods. Sixty patients with ulcerative colitis were examined, among them there were 31 (51.7 %) men and 29 (48.3 %) women with mean age of (40.28 ± 1.34) years. The comparison group consisted of 20 patients with irritable bowel syndrome. By means of enzyme immunoassay using a StatFax 303 Plus analyzer (USA) with Immundiagnostik (Germany) test kit, we determined the level of fecal myeloperoxidase, the content of α1-antitrypsin in the blood serum and feces, and the level of fecal calprotectin using a Buhlmann test kit (Switzerland). Results. Fecal myeloperoxidase and calprotectin are specific markers of intestinal inflammation, which is confirmed by established correlations between the endoscopic activity of intestinal inflammation and its content: r = 0.632; p < 0.05, and r = 0.532; p < 0.05, respectively. The concentration of α1-antitrypsin in the feces of men is 3 times higher than that in women (p < 0.05), and, on the contrary, the level of α1-antitrypsin in the blood is higher in female patients compared to men (p < 0.05). The discovered correlation between the content of α1-antitrypsin in the feces and the male gender (r = 0.528; p

Background. The issue of the prevalence of opportunistic infections in persons with inflammatory bowel disease (IBD) remains relevant. Among opportunistic infections, in particular, we would like to note Herpesviridae family (herpes simplex virus type 1 and 2), human herpesvirus type 3 (varicella zoster virus), human herpesvirus type 4 (Epstein-Barr virus), cytomegalovirus (CMV), or human herpesvirus type 5, human herpesvirus type 6 and parvovirus B19. Clinically marked herpes and parvovirus infections are frequent causes of systemic inflammation of the gastrointestinal tract. This is a serious problem, especially for persons with long-term immunosuppression, who have IBD, and special attention in this aspect is paid to cytomegalovirus infection. Clinical activity of CMV-associated IBD, its duration and severity, as well as the use of steroids and anti-TNF-α agents were identified as risk factors for adverse outcomes. It is important not only to detect the presence of viruses in the patient’s body, but also to clarify their etiological role in the development of the disease. According to the current European Crohn’s and Colitis Organisation (ECCO) protocols, all patients with IBD are recommended to be screened in hormone resistance, loss of effect from maintenance therapy and severe attacks of the disease. The addition of active CMV infection to IBD may likely be one of the causes of resistance to hormone and immunosuppressive therapy, as well as biological drugs, but this issue requires further researches. The purpose was to evaluate the frequency of detecting isolated cytomegalovirus infection and mixed (herpes and parvovirus B19) viral infections in patients with IBD and their influence on the disease activity. Materials and methods. One hundred and eighty-nine patients (98 women and 91 men) with IBD (102 with ulcerative colitis (UC) and 87 with Crohn’s disease (CD)) were examined. The age of patients was from 16 to 63 years (mean age (41.4 ± 4.8) years). In addition to standard clinical endoscopic examinations according to ECCO guidelines, disease activity was assessed by indicators of highly sensitive C-reactive protein, homocysteine, vitamin D in blood serum, albumin in urine, calprotectin and lactoferrin in feces. All patients underwent serological blood test by enzyme-linked immunosorbent assay for specific antibodies to herpesviruses and IgG/IgM antibodies to parvovirus B19, determination of DNA of herpes simplex viruses types 1, 2, 6, Epstein-Barr virus, cytomegalovirus, herpes zoster by a polymerase chain reaction in blood and tissues. All patients underwent determination of blood cytokines (tumor necrosis factor α, interleukins 1β, -2, -4, -6, -8, -10, -18). Results. Viral (herpes and parvovirus B19) infections in patients with IBD occurred in 81 cases (42.8 %): in 35 (40.2 %) of 87 patients with CD and in 46 (45.0 %) of 102 — with UC. Among patients with cytomegalovirus infection alone, 21 (11.1 % of the total number and 25.9 % of infected persons) suffered from UC and 16 (8.5 % of the total number and 19.7 % of infected persons) — from CD. In 26 (13.8 % of the total number and 32.1 % of infected persons) cases, mixed viral infections were detected — in 13 patients with CD and 13 with UC (6.9 % of the total number and 16.0 % of infected persons). In patients with IBD, the frequency of detecting isolated cytomegalovirus infection is 19.5 % of the total number and 45.6 % of infected persons; mixed viral infection was found in 13.8 % of the total number and 32.1 % of infected patients. The clinical endoscopic picture (resistance to basic therapy, the mismatch between the endoscopic picture and the pathomorphological conclusion), as well as laboratory data, indicate a more severe course of diseases in the presence of cytomegalovirus infection. Conclusion. The data obtained allow us to recommend, in addition to ECCO protocols, the determination of the presence of opportunistic (herpes and parvovirus B19) infections in patients with newly diagnosed IBD before starting basic therapy, without waiting for the development of disease forms refractory to therapy., Актуальность. Вопрос распространенности оппортунистических инфекций у лиц с воспалительными заболеваниями кишечника (ВЗК) остается актуальным. Особое внимание среди оппортунистических инфекций уделяется цитомегаловирусной (ЦМВ) инфекции. Клиническая активность ЦМВ-ассоциированного ВЗК, его длительность и степень тяжести, а также использование стероидов и анти-ФНО-α-агентов были идентифицированы как факторы риска неблагоприятных исходов. В диагностике ЦМВ важно не просто выявить наличие вируса в организме пациента, но и уточнить его этиологическую роль в развитии заболевания. В настоящее время рекомендуется проведение скрининга на ЦМВ у всех пациентов с ВЗК при гормональной резистентности, потере эффекта от поддерживающей терапии и при тяжелых эпизодах заболевания. Цель исследования: оценка частоты выявления изолированной цитомегаловирусной инфекции и смешанных (герпес и парвовирус В19) вирусных инфекций у пациентов с ВЗК и их влияние на активность заболевания. Материалы и методы. Обследовано 189 пациентов с ВЗК, 102 с язвенным колитом и 87 с болезнью Крона, среди них 98 женщин и 91 мужчина. Возраст пациентов составлял от 16 до 63 лет, в среднем (41,4 ± 4,8) года. Кроме стандартного клинико-эндоскопического обследования в соответствии с положениями Европейской организации по изучению болезни Крона и язвенного колита (ЕССО), активность заболевания оценивалась по показателям высокочувствительного С-реактивного белка, гомоцистеина, витамина D в сыворотке крови, альбумина в моче, кальпротектина и лактоферрина в кале. Всем пациентам проведено серологическое исследование крови методом иммуноферментного анализа на специфические антитела к герпесвирусам и IgG-/IgM-антитела к парвовирусу В19, а также определение ДНК вирусов простого герпеса 1, 2, 6-го типов, вируса Эпштейна — Барр, цитомегаловируса, герпеса зостер методом полимеразной цепной реакции. У всех пациентов также определяли уровни цитокинов в крови (фактор некроза опухоли α, интерлейкины 1β, -2, -4, -6, -8, -10, -18). Результаты. У пациентов с ВЗК частота выявления изолированной цитомегаловирусной инфекции составляет, по нашим данным, 19,5 %, а с учетом смешанных поражений — 29,6 %. Клинико-эндоскопическая картина (рефрактерность к базисной терапии, несоответствие между эндоскопической картиной и патоморфологическим заключением), а также данные лабораторных исследований указывают на более тяжелое течение заболевания при наличии цитомегаловирусной инфекции. Выводы. Полученные данные позволяют нам рекомендовать в дополнение к протоколам ЕССО определение наличия оппортунистических инфекций у пациентов с впервые выявленным ВЗК до начала базисной терапии, не дожидаясь развития рефрактерных к лечению форм заболевания., Актуальність. Питання поширеності опортуністичних інфекцій в осіб iз запальними захворюваннями кишечника (ЗЗК) залишається актуальним. Особливу увагу серед опортуністичних інфекцій приділяється цитомегаловірусній (ЦМВ) інфекції. Клінічна активність ЦМВ-асоційованого ЗЗК, його тривалість і ступінь тяжкості, а також використання стероїдів і анти-ФНП-α-агентів були ідентифіковані як фактори ризику несприятливих наслідків. У діагностиці ЦМВ важливо не просто виявити наявність вірусу в організмі пацієнта, але й уточнити його етіологічну роль у розвитку захворювання. У цей час рекомендується проведення скринінгу на ЦМВ у всіх пацієнтів iз ЗЗК при гормональній резистентності, втрати ефекту від підтримуючої терапії та при тяжких епізодах захворювання. Мета дослідження: оцінка частоти виявлення ізольованої цитомегаловірусної інфекції і змішаних (герпес та парвовірус В19) вірусних інфекцій у пацієнтів iз ЗЗК та їх вплив на активність захворювання. Матеріали та методи. Обстежено 189 осіб iз ЗЗК, 102 з виразковим колітом і 87 з хворобою Крона, серед них 98 жінок та 91 чоловік. Вік пацієнтів становив від 16 до 63 років, у середньому (41,4 ± 4,8) року. Крім стандартного клініко-ендоскопічного обстеження відповідно до положень Європейської організації з вивчення хвороби Крона і виразкового коліту (ЕССО), активність захворювання оцінювалася за показниками високочутливого С-реактивного білка, гомоцистеїну, вітаміну D у сироватці крові, альбуміну в сечі, кальпротектину і лактоферину в калі. Усім пацієнтам проведено серологічне дослідження крові методом імуноферментного аналізу на специфічні антитіла до герпесвірусів і IgG-/IgM-антитіла до парвовірусу В19, а також визначення ДНК вірусів простого герпесу 1, 2, 6-го типів, вірусу Епштейна — Барр, цитомегаловірусу, герпесу зостер методом полімеразної ланцюгової реакції. В усіх пацієнтів також визначали рівні цитокінів у крові (фактор некрозу пухлини α, інтерлейкіни 1β, -2, -4, -6, -8, -10, -18). Результати. У пацієнтів iз ЗЗК частота виявлення ізольованої цитомегаловірусної інфекції становить, за нашими даними, 19,5 %, а з урахуванням змішаних уражень — 29,6 %. Клініко-ендоскопічна картина (рефрактерність до базисної терапії, невідповідність між ендоскопічною картиною і патоморфологічним висновком), а також дані лабораторних досліджень вказують на більш тяжкий перебіг захворювання за наявності цитомегаловірусної інфекції. Висновки. Отримані дані дозволяють нам рекомендувати на додаток до протоколiв ЕССО визначення наявності опортуністичних інфекцій у пацієнтів iз вперше виявленим ЗЗК до початку базисної терапії, не чекаючи на розвиток рефрактерних до лiкування форм захворювання.

Background. The purpose was to evaluate the aggressive and protective properties of gastric juice depending on the severity of pyloroduodenal stenosis in patients with severe peptic ulcer disease. Materials and methods. In 2014–2019, 157 patients with different degrees of pyloroduodenal stenosis of ulcerative origin were examined at the Department of Surgery of the Digestive Organs of the State Institution “Institute of Gastroenterology of the National Academy of Medical Sciences of Ukraine”. Of these, 92 patients with compensated and subcompensated degree of stenosis were selected for the study of gastric acid and mucus production, among which there were 71 men and 21 women aged 38–56 years, mean age (45.3 ± 5.2) years. Patients were divided into 2 groups depending on the degree of stenosis: group 1 — 57 persons with compensated stenosis, group 2 — 35 patients with subcompensated stenosis. The control group consisted of 20 apparently healthy individuals. In gastric contents, we determined: pH level, concentration of pepsin, glycoproteins, hexosamines, fucose, sialic acids. Results. Analysis of the levels of acid and mucus production in piloroduodenal stenosis of varying severity showed that in patients with subcompensated stenosis, there was an increase in the frequency of hyperacid secretion by 21.1 % (p

Background. Changes in the intestinal microbiome trigger the development and progression of non-alcoholic fatty liver disease (NAFLD). Adverse fluctuations in intestinal microbiota are associated with increased intestinal permeability, activation of mucosal and adaptive immunity, increase in production and intestinal absorption of short-chain fatty acids (SCFA). The ratio of acetic, propionic, butyric acid is an important indicator of the integrity of the microbial community of the intestine. Thus, the study of the gut microbiota composition and short-chain fatty acids production represents a very appealing approach to increasing our knowledge about the mechanisms leading to NAFLD in children. The purpose of the study was to determine the features of the fecal short-chain fatty acids (fSCFA) content and the colonic microbiota composition in children with NAFLD. Materials and methods. A comprehensive examination of 102 children was provided in the Department of Pediatric Gastroenterology of the Institute of Gastroenterology of the National Academy of Medical Sciences of Ukraine. According to the presence of obesity, transient elastography data and alanine aminotransferase levels the patients were divided into four groups: I group — children with simple hepatic steatosis (n = 24); II group — children with nonalcoholic steatohepatitis (NASH) (n = 14); III group — children with obesity without steatosis (n = 48), IV group — children with normal weight (n = 16). Chromatographic study of fSCFA was conducted using gas chromatograph Chromatec-Crystal 5000. The microorganisms were identified using a microbiological study of the colon content. Diagnosis of NAFLD was established with FibroScan 502 Touch (Echosens, France) with the determination of the controlled attenuation parameter. Results. Significant changes in the spectrum of fSCFA were observed in children of the III group with acetic acid content increased by 4.8 times (р

Background. Gastric cancer (GC) is considered an urgent problem of oncology, due to its high incidence and morta­lity, diagnosis at a later stage of the disease progression, anatomical and topographical features of the organ affected by the tumor and the low effectiveness of the existing methods of treatment. The role of purine dysmetabolism in carcinogenesis remains insufficiently studied, and its clinical significance requires clarification. An increased level of uric acid in the blood is a risk factor for the deve­lopment and further severe course of gastric cancer. Purine bases are considered to belong to the tumor biomarkers; however, their diagnostic and prognostic significance in GC remains uninvestigated. The purpose was to assess the state of purine metabolism in patients with gastric cancer, to establish the clinical and pathogenetic significance of the identified changes. Materials and me­thods. A total of 88 patients with cancer (all men) aged from 29 to 79 years (mean age 60 years) were analyzed. Localization of the tumor process occurred in the stomach pylorus in 76 % cases, in the body — in 16 %, in the antrum — in 3 %, and in 2 % of all cases examined the entire stomach was affected. Adenocarcinoma was diagnosed in 72 % of cases, undifferentiated adenogenic stomach cancer — in 18 %, squamous cancer — in 8 %, colloid GC — in 2 %. The ratio of IA, IB, IIA, IIB, IIIA, IIIB and IV stages of the GC was 1 : 3 : 9 : 12 : 6 : 5 : 6. The tumor spread to the spleen was found in 15 % of cases, the pancreas — in 7 %, the liver — 6 %, the esophagus — 3 %, the diaphragm — 2 %, the gallbladder — 1 %. Lymph node metastases were found in 60 % of the GC observations, distant metastases — in 14 %. The blood serum levels of products of purine metabolism — uric acid, hydroxypurinol, adenine, guanine, xanthine, hypoxanthine, xanthine oxidase, xanthine deaminase, adenosine deaminase, and 5'-nucleotidase activities were stu­died. Results. The changes in purine metabolism were found in all patients with gastric cancer, including compared with the control group of healthy people, the level of uric acid was 2.0 times higher, oxypurinol 4.5 times higher, adenine — by 16 %, xanthine oxidase activity by 2.1 times, xanthine deaminase — by 33 % and adenosine deaminase — by 7.1 times, the elevated rates of which were found in 99, 84, 39, 90, 53 and 100 % of cases, respectively, depending on the severity of the tumor process, total lesion of the stomach, spread of the tumor to the liver, pancreas, and esophagus, the presence of metastases in para-aortic lymph nodes, liver, lung, bones and brain. The altered purine metabolism worsens three-year survival of patients against the background of surgical, medical, and radiation treatment. Conclusion. Changes in purine metabolism are involved in the pathogenetic constructions of the GC, reflect the peculiarities of the course of the tumor process; and the parameters of uric acid and adenine have prognostic significance.

Background and Aims Increasing evidence supports the role of early-life gut microbiota in developing atopic diseases, but ecological changes to gut microbiota during infancy in relation to food sensitization remain unclear. We aimed to characterize and associate these changes with the development of food sensitization in children. Methods In this observational study, using 16S rRNA amplicon sequencing, we characterized the composition of 2844 fecal microbiota in 1422 Canadian full-term infants. Atopic sensitization outcomes were measured by skin prick tests at age 1 year and 3 years. The association between gut microbiota trajectories, based on longitudinal shifts in community clusters, and atopic sensitization outcomes at age 1 and 3 years were determined. Ethnicity and early-life exposures influencing microbiota trajectories were initially examined, and post-hoc analyses were conducted. Results Four identified developmental trajectories of gut microbiota were shaped by birth mode and varied by ethnicity. The trajectory with persistently low Bacteroides abundance and high Enterobacteriaceae/Bacteroidaceae ratio throughout infancy increased the risk of sensitization to food allergens, particularly to peanuts at age 3 years by 3-fold (adjusted odds ratio [OR] 2.82, 95% confidence interval [CI] 1.13–7.01). A much higher likelihood for peanut sensitization was found if infants with this trajectory were born to Asian mothers (adjusted OR 7.87, 95% CI 2.75–22.55). It was characterized by a deficiency in sphingolipid metabolism and persistent Clostridioides difficile colonization. Importantly, this trajectory of depleted Bacteroides abundance mediated the association between Asian ethnicity and food sensitization. Conclusions This study documented an association between persistently low gut Bacteroides abundance throughout infancy and sensitization to peanuts in childhood. It is the first to show a mediation role for infant gut microbiota in ethnicity-associated development of food sensitization.

Background and Aims Bacterial swarming, a collective movement on a surface, has rarely been associated with human pathophysiology. This study aims to define a role for bacterial swarmers in amelioration of intestinal stress. Methods We developed a polymicrobial plate agar assay to detect swarming and screened mice and humans with intestinal stress and inflammation. From chemically induced colitis in mice, as well as humans with inflammatory bowel disease, we developed techniques to isolate the dominant swarmers. We developed swarm-deficient but growth and swim-competent mutant bacteria as isogenic controls. We performed bacterial reinoculation studies in mice with colitis, fecal 16S, and meta-transcriptomic analyses, as well as in vitro microbial interaction studies. Results We show that bacterial swarmers are highly predictive of intestinal stress in mice and humans. We isolated a novel Enterobacter swarming strain, SM3, from mouse feces. SM3 and other known commensal swarmers, in contrast to their mutant strains, abrogated intestinal inflammation in mice. Treatment of colitic mice with SM3, but not its mutants, enriched beneficial fecal anaerobes belonging to the family of Bacteroidales S24-7. We observed SM3 swarming associated pathways in the in vivo fecal meta-transcriptomes. In vitro growth of S24-7 was enriched in presence of SM3 or its mutants; however, because SM3, but not mutants, induced S24-7 in vivo, we concluded that swarming plays an essential role in disseminating SM3 in vivo. Conclusions Overall, our work identified a new but counterintuitive paradigm in which intestinal stress allows for the emergence of swarming bacteria; however, these bacteria act to heal intestinal inflammation.

The article presents the results of study of the degree of contamination of the gastric mucosa with Helicobacter pylori infection and its relationship with duodenogastric reflux. There was revealed a direct correlation between the bile acids level in the gastric acid, and the presence of Helicobacter pylori, that in combination with duodenogastric reflux negatively affect the state of the gastric mucosa.

The cancer stem cell (CSC) concept emerged from the recognition of inherent tumor heterogeneity and suggests that within a given tumor, in analogy to normal tissues, there exists a cellular hierarchy composed of a minority of more primitive cells with enhanced longevity (ie, CSCs) that give rise to shorter-lived, more differentiated cells (ie, cancer bulk populations), which on their own are not capable of tumor perpetuation. CSCs can be responsible for cancer therapeutic resistance to conventional, targeted, and immunotherapeutic treatment modalities, and for cancer progression through CSC-intrinsic molecular mechanisms. The existence of CSCs in colorectal cancer (CRC) was first established through demonstration of enhanced clonogenicity and tumor-forming capacity of this cell subset in human-to-mouse tumor xenotransplantation experiments and subsequently confirmed through lineage-tracing studies in mice. Surface markers for CRC CSC identification and their prospective isolation are now established. Therefore, the application of single-cell omics technologies to CSC characterization, including whole-genome sequencing, RNA sequencing, and epigenetic analyses, opens unprecedented opportunities to discover novel targetable molecular pathways and hence to develop novel strategies for CRC eradication. We review recent advances in this field and discuss the potential implications of next-generation CSC analyses for currently approved and experimental targeted CRC therapies.

Background & Aims Altered gut microbiota composition and function have been associated with inflammatory bowel diseases, including ulcerative colitis (UC), but the causality and mechanisms remain unknown. Methods We applied 16S ribosomal RNA gene sequencing, shotgun metagenomic sequencing, in vitro functional assays, and gnotobiotic colonizations to define the microbial composition and function in fecal samples obtained from a cohort of healthy individuals at risk for inflammatory bowel diseases (pre-UC) who later developed UC (post-UC) and matched healthy control individuals (HCs). Results Microbiota composition of post-UC samples was different from HC and pre-UC samples; however, functional analysis showed increased fecal proteolytic and elastase activity before UC onset. Metagenomics identified more than 22,000 gene families that were significantly different between HC, pre-UC, and post-UC samples. Of these, 237 related to proteases and peptidases, suggesting a bacterial component to the pre-UC proteolytic signature. Elastase activity inversely correlated with the relative abundance of Adlercreutzia and other potentially beneficial taxa and directly correlated with known proteolytic taxa, such as Bacteroides vulgatus. High elastase activity was confirmed in Bacteroides isolates from fecal samples. The bacterial contribution and functional significance of the proteolytic signature were investigated in germ-free adult mice and in dams colonized with HC, pre-UC, or post-UC microbiota. Mice colonized with or born from pre-UC–colonized dams developed higher fecal proteolytic activity and an inflammatory immune tone compared with HC-colonized mice. Conclusions We have identified increased fecal proteolytic activity that precedes the clinical diagnosis of UC and associates with gut microbiota changes. This proteolytic signature may constitute a noninvasive biomarker of inflammation to monitor at-risk populations that can be targeted therapeutically with antiproteases.

Background and Aims Diffuse-type gastric cancer (GC) is currently subdivided into signet-ring cell carcinoma (SRCC) and non-SRCC, referred to as poorly cohesive carcinoma not otherwise specified (PCC-NOS). Although these subtypes are considered to be independent, they often coexist in the same tumors, raising a question of whether they clonally differ or not. To tackle this question, we established an experimental platform for human diffuse GC that enables accurate modeling of histologic subtypes. Methods Seven patient-derived diffuse GC organoid lines were established, characterized by histopathologic analysis, in situ hybridization, and gene expression analysis. For genetic modeling of diffuse GC, we knocked out CDH1 and/or TP53 in human normal gastric organoids. Green fluorescent protein–labeled GC organoids were xenotransplanted into immune-deficient mice for in vivo assessment. Results PCC-NOS organoids transformed into SRCC-like structures on removal of Wnt and R-spondin from the culture medium. This morphologic change paralleled downregulation of Wnt-target and gastric stem cell genes, including LGR5, and elevation of differentiation markers, such as KRT20 and MUCs. The association between Wnt target gene expression and histologic subtypes was confirmed in 3 patient-derived GC tissues. In vivo, single clone-derived organoids formed tumors that comprised 2 distinct histologic compartments, each corresponding to SRCC and PCC-NOS. The transition from PCC-NOS to SRCC histology reflected the abundance of surrounding R-spondin–expressing fibroblasts. Conclusions SRCC and PCC-NOS were clonally identical, and their morphology was regulated by extracellular Wnt and R-spondin expression. Our results decoded how genetic mutations and the tumor environment shape pathohistologic and biologic phenotypes in human diffuse GCs.

The article presents a case report of ascariasis in a 60-year-old woman, which was not revealed during coprological survey. In addition, there were no indirect signs of parasitic infestation as an increased level of blood eosinophils. The diagnosis was established through irrigography and detection of antibodies to ascarides in the blood serum by means of enzyme immunoassay., Приведен случай аскаридоза у 60-летней женщины, который не выявлялся при копрологическом исследовании. Кроме этого, отсутствовали косвенные признаки паразитарной инвазии в виде увеличения содержания эозинофилов крови. Диагноз был выставлен благодаря ирригографии и выявлению антител к аскаридам в сыворотке крови методом иммуноферментного анализа., Наведений клінічний випадок аскаридозу у 60-річної жінки, що не був виявлений при копрологічному дослідженні. Крім того, були відсутніми непрямі ознаки паразитарної інвазії у вигляді збільшення вмісту еозинофілів крові. Діагноз був встановлений завдяки іригографії та наявності антитіл до аскарид у сироватці крові за методом імуноферментного аналізу.

Medical and recreational cannabis use has increased dramatically over the last decade, resulting from mainstream cultural acceptance and legalization in several countries worldwide. Cannabis and its derivatives affect many gastrointestinal processes via the endocannabinoid system (ECS). The ECS influences gastrointestinal homeostasis through anti-inflammatory, anti-nociceptive, and anti-secretory effects. Some gastrointestinal disorders might therefore be treated with cannabinoids. Despite numerous studies in cell lines and animals, few human studies have evaluated the therapeutic effects of cannabinoids. Cannabis' schedule 1 drug status has limited its availability in research; cannabis has been legalized only recently, in some states, for medicinal and/or recreational use. Cannabinoids can alleviate chemotherapy-induced nausea and emesis and chronic pain. Studies have demonstrated the important roles of the ECS in metabolism, obesity, and nonalcoholic fatty liver disease and the anti-inflammatory effects of cannabis have been investigated in patients with inflammatory bowel diseases. Despite its potential benefits, undesired or even detrimental effects of cannabis can limit its use. Side effects such as cannabinoid hyperemesis syndrome affect some users. We review the ECS and the effects of cannabis and its derivatives on gastrointestinal and hepatic function in health and disease.

Background & Aims Biomarkers are needed to identify patients at risk for development of inflammatory bowel diseases. We aimed to identify serum biomarkers of Crohn's disease and ulcerative colitis that can be detected and quantified before diagnosis. Methods We obtained serum samples from patients archived before a diagnosis of Crohn's disease (n = 200) or ulcerative colitis (n = 199), as well as from 200 healthy individuals (controls), collected from 1998 through 2013 as part of the US Defense Medical Surveillance System. We measured levels of antibodies against microbes (anti–Saccharomyces cerevisiae IgA or IgG, anti–Escherichia coli outer membrane porin C, anti-CBir1, anti-flagellin 2, anti-flagellin X, and perinuclear anti-neutrophil cytoplasmic antibodies) and 1129 proteins in each sample. We then used functional principal component analysis to derive the time-varying trajectory for each marker, which then was used in a multivariate model to predict disease status. Predictive performances at different prediagnosis timepoints were evaluated using area under the receiver operating characteristic curves (AUROCs). Biological pathways that were up-regulated in serum from patients with Crohn's disease were identified based on changes in protein abundance at different time periods preceding diagnosis. Results We identified a panel of 51 protein biomarkers that were predictive of Crohn's disease within 5 years with an AUROC of 0.76 and a diagnosis within 1 year with an AUROC of 0.87. Based on the proteins included in the panel, imminent development of CD was associated with changes in the complement cascade, lysosomes, innate immune response, and glycosaminoglycan metabolism. Serum antibodies and proteins identified patients who received a diagnosis of ulcerative colitis within 5 years with an AUROC of only 0.56 and within 1 year with an AUROC of 0.72. Conclusions We identified a panel of serum antibodies and proteins that were predictive of patients who will receive a diagnosis of Crohn's disease within 5 years with high accuracy. By contrast we did not identify biomarkers associated with future diagnosis of ulcerative colitis.

BACKGROUND & AIMS: Establishment of the gastrointestinal microbiota during infancy affects immune system development and oral tolerance induction. Perturbations in the microbiome during this period can contribute to development of immune-mediated diseases. We monitored microbiota maturation and associations with subsequent development of allergies in infants and children. METHODS: We collected 1453 stool samples, at 5, 13, 21, and 31weeks postpartum (infants), and once at school age (6-11 years), from 440 children (49.3% girls, 24.8% born by cesarean delivery; all children except for 6 were breastfed for varying durations; median 40 weeks; interquartile range, 30-53 weeks). Microbiota were analyzed by amplicon sequencing. Children were followed through 3 years of age for development of atopic dermatitis; data on allergic sensitization and asthma were collected when children were school age. RESULTS: Diversity of fecal microbiota, assessed by Shannon index, did not differ significantly among children from 5 through 13 weeks after birth, but thereafter gradually increased to 21 and 31 weeks. Most bacteria within the Bacteroidetes and Proteobacteria phyla were already present at 5 weeks after birth, whereas many bacteria of the Firmicutes phylum were acquired at later times in infancy. At school age, many new Actinobacteria, Firmicutes, and Bacteroidetes bacterial taxa emerged. The largest increase in microbial diversity occurred after 31 weeks. Vaginal, compared with cesarean delivery, was most strongly associated with an enrichment of Bacteroides species at 5 weeks through 31 weeks. From 13 weeks onward, diet became the most important determinant of microbiota composition; cessation of breast-feeding, rather than solid food introduction, was associated with changes. For example, Bifidobacteria, staphylococci, and streptococci significantly decreased on cessation of breastfeeding, whereas bacteria within the Lachnospiraceae family (Pseudobutyrivibrio, Lachnobacterium, Roseburia, and Blautia) increased. When we adjusted for confounding factors, we found fecal microbiota composition to be associated with development of atopic dermatitis, allergic sensitization, and asthma. Members of the Lachnospiraceae family, as well as the genera Faecalibacterium and Dialister, were associated with a reduced risk of atopy. CONCLUSIONS: In a longitudinal study of fecal microbiota of children from 5 weeks through 6 to 11 years, we tracked changes in diversity and composition associated with the development of allergies and asthma.

SUMMARY Our gastrointestinal tract is colonized by trillions of microbes. There is growing recognition that commensal bacteria can promote the development of colorectal adenomas and cancer. For example, bacterial plaques are strongly associated with adenomas in familial adenomatous polyposis (Science 2018;359:592-597), and fusobacterium is associated with colorectal cancer liver metastasis.(Science 2017;358:1443-1448)

Background and aims Due to the high load of immunogenic frameshift neoantigens, tumors arising in individuals with Lynch syndrome (LS), the most common inherited colorectal cancer (CRC) syndrome, are characterized by a pronounced immune infiltration. However, the immune status of normal colorectal mucosa in LS is not well characterized. We assessed the immune infiltrate in tumor-distant normal colorectal mucosa from LS CRC patients, sporadic microsatellite-unstable (MSI) and microsatellite-stable (MSS) CRC patients, and cancer-free LS carriers. Methods CD3-positive, FOXP3-positive and CD8-positive T cells were quantified in 219, 233 and 201 formalin-fixed paraffin-embedded (FFPE) normal colonic mucosa tissue sections from CRC patients and LS cancer-free carriers and 26, 22 and 19 LS CRCs, respectively. CD3-positive T cells were also quantified in an independent cohort of 97 FFPE normal rectal mucosa tissue sections from LS carriers enrolled on the CAPP2 clinical trial. The expression of 770 immune-relevant genes was analyzed in a subset of samples using the NanoString nCounter platform. Results LS normal mucosa specimens showed significantly elevated CD3-, FOXP3- and CD8-positive T cell densities compared to non-LS controls. Gene expression profiling and cluster analysis revealed distinct immune profiles in LS carrier mucosa with and without cancer manifestation. Long term follow-up of LS carriers within the CAPP2 trial found a correlation between mucosal T cell infiltrate and time to subsequent tumor occurrence. Conclusion LS carriers show elevated mucosal T cell infiltration even in the absence of cancer. The normal mucosa immune profile may be a temporary or permanent tumor risk modifier in LS carriers.

Celiac disease (CeD) is a frequent immune-mediated disease that affects not only the small intestine but also many extraintestinal sites. The role of gluten proteins as dietary triggers, HLA-DQ2 or -DQ8 as major necessary genetic predisposition, and tissue transglutaminase (TG2) as mechanistically involved autoantigen, are unique features of CeD. Recent research implicates many cofactors working in synergism with these key triggers, including the intestinal microbiota and their metabolites, nongluten dietary triggers, intestinal barrier defects, novel immune cell phenotypes, and mediators and cytokines. In addition, apart from HLA-DQ2 and -DQ8, multiple and complex predisposing genetic factors and interactions have been defined, most of which overlap with predispositions in other, usually autoimmune, diseases that are linked to CeD. The resultant better understanding of CeD pathogenesis, and its manifold manifestations has already paved the way for novel therapeutic approaches beyond the lifelong strict gluten-free diet, which poses a burden to patients and often does not lead to complete mucosal healing. Thus, supported by improved mouse models for CeD and in vitro organoid cultures, several targeted therapies are in phase 2–3 clinical studies, such as highly effective gluten-degrading oral enzymes, inhibition of TG2, cytokine therapies, induction of tolerance to gluten ingestion, along with adjunctive and preventive approaches using beneficial probiotics and micronutrients. These developments are supported by novel noninvasive markers of CeD severity and activity that may be used as companion diagnostics, allow easy-to perform and reliable monitoring of patients, and finally support personalized therapy for CeD.

Background & Aims Enterotoxigenic Bacteroides fragilis (ETBF) is strongly associated with the occurrence of inflammatory bowel disease (IBD), colitis-associated colorectal cancer, and colorectal cancer (CRC). However, the mechanism of ETBF-induced intestinal inflammation and tumorigenesis remains unclear. Methods microRNA sequencing was used to detect the differentially expressed microRNAs in both ETBF-treated cells and exosomes derived from ETBF-inoculated cells. Cell Counting Kit 8 assays were used to evaluate the effect of ETBF and exosomes on CRC cell proliferation. The biological role and mechanism of ETBF-mediated miR-149-3p in colitis and colon carcinogenesis were determined both in vitro and in vivo. Results ETBF promoted CRC cell proliferation by down-regulating miR-149-3p both in vitro and in vivo. ETBF–down-regulated miR-149-3p depended on METTL14-mediated N6-methyladenosine methylation. As the target gene of miR-149-3p, PHF5A transactivated SOD2 through regulating KAT2A messenger RNA alternative splicing after ETBF treatment in CRC cells. miR-149-3p could be released in exosomes and mediated intercellular communication by modulating T-helper type 17 cell differentiation. The level of plasma exosomal miR-149-3p was gradually decreased from healthy control individuals to patients with IBD and CRC. miR-149-3p, existing in plasma exosomes, negatively correlated with the abundance of ETBF in patients with IBD and CRC. Conclusions Exosomal miR-149-3p derived from ETBF-treated cells facilitated T-helper type 17 cell differentiation. ETBF-induced colorectal carcinogenesis depended on down-regulating miR-149-3p and further promoting PHF5A-mediated RNA alternative splicing of KAT2A in CRC cells. Targeting the ETBF/miR-149-3p pathway presents a promising approach to treat patients with intestinal inflammation and CRC with a high amount of ETBF.

Background & Aims Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor that is almost uniformly lethal in humans. Activating mutations of KRAS are found in >90% of human PDACs and are sufficient to promote acinar-to-ductal metaplasia (ADM) during tumor initiation. The roles of miRNAs in oncogenic Kras-induced ADM are incompletely understood. Methods The Ptf1aCre/+ LSL-KrasG12D/+ and Ptf1aCre/+ LSL-KrasG12D/+ LSL-p53R172H/+ and cerulein-induced acute pancreatitis mice models were used. mir-802 was conditionally ablated in acinar cells to study the function of miR-802 in ADM. Results We show that miR-802 is a highly abundant and acinar-enriched pancreatic miRNA that is silenced during early stages of injury or oncogenic KrasG12D-induced transformation. Genetic ablation of mir-802 cooperates with KrasG12D by promoting ADM formation. miR-802 deficiency results in de-repression of the miR-802 targets Arhgef12, RhoA, and Sdc4, activation of RhoA, and induction of the downstream RhoA effectors ROCK1, LIMK1, COFILIN1, and EZRIN, thereby increasing F-actin rearrangement. mir-802 ablation also activates SOX9, resulting in augmented levels of ductal and attenuated expression of acinar identity genes. Consistently with these findings, we show that this miR-802–RhoA–F-actin network is activated in biopsies of pancreatic cancer patients and correlates with poor survival. Conclusions We show miR-802 suppresses pancreatic cancer initiation by repressing oncogenic Kras-induced ADM. The role of miR-802 in ADM fills the gap in our understanding of oncogenic Kras-induced F-actin reorganization, acinar reprogramming, and PDAC initiation. Modulation of the miR-802–RhoA–F-actin network may be a new strategy to interfere with pancreatic carcinogenesis.